(R)-4-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile | 1022981-69-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (R)-4-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile
• 英文别名: 4-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]benzonitrile
• CAS: 1022981-69-6
• 化学式: C₂₃H₁₈FN₅
• 分子量: 383.428
• InChiKey: NNDVLAPMFXYAAS-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-(6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile 在 ChiralPal AD-H column 作用下， 以 正己烷 、 异丙醇 为溶剂， 生成 (R)-4-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile 、 (S)-4-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile
  参考文献：
  名称：

  (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

  摘要：

  Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

  DOI：

  10.1021/acsmedchemlett.5b00050

文献信息

• [EN] SUBSTITUTED IMIDAZO[1,2B]PYRIDAZINE COMPOUNDS AS TRK KINASE INHIBITORS<br/>[FR] COMPOSÉS IMIDAZO[1,2B]PYRIDAZINE SUBSTITUÉS COMME INHIBITEURS DE KINASES TRK
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2010033941A1

  公开（公告）日：2010-03-25

  Compounds of Formula (I): in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

  式（I）化合物：其中R1、R2、R3、R4、X、Y和n的含义如规范中所述，是Trk激酶的抑制剂，并且在治疗可以使用Trk激酶抑制剂治疗的疾病中是有用的。
• Heterocyclic compounds as antiinflammatory agents
  申请人：Ferrand Sandrine

  公开号：US20100041662A1

  公开（公告）日：2010-02-18

  A compound of Formula Ia or Ib in free or salt or solvate form, where R 1 , R 2 , R 3 , R 4 , R 5 R 20 , R 24 , R 25 , X, Y and Z have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. These compounds are also useful for treating diseases mediated by the Pi3 k receptor, the JAK-2 receptor and the TRK receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

  公式Ia或Ib的化合物以自由或盐或溶剂形式存在，其中R1、R2、R3、R4、R5R20、R24、R25、X、Y和Z的含义如规范所示，可用于治疗由ALK-5和/或ALK-4受体介导的疾病。这些化合物还可用于治疗由Pi3kreceptor、JAK-2受体和TRK受体介导的疾病。还描述了含有这些化合物的制药组合物和制备这些化合物的方法。
• SUBSTITUTED IMIDAZO[1,2b]PYRIDAZINE COMPOUNDS AS TRK KINASE INHIBITORS
  申请人：Andrews Steven W.

  公开号：US20110166122A1

  公开（公告）日：2011-07-07

  Compounds of Formula (I): in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

  式(I)的化合物：其中R1、R2、R3、R4、X、Y和n具有规范中给出的含义，是Trk激酶的抑制剂，可用于治疗可用Trk激酶抑制剂治疗的疾病。
• FUSED NITROGEN CONTAINING HETEROCYCLES AND COMPOSITIONS THEREOF AS KINASE INHIBITORS
  申请人：Albaugh Pamela A.

  公开号：US20110166133A1

  公开（公告）日：2011-07-07

  The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, C-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-IR, ALK4, ALK5 and ALK or combinations thereof.

  该发明提供了化合物、包含这些化合物的药物组成物以及使用这些化合物治疗或预防与异常或非规则激酶活性相关的疾病或障碍的方法，特别是Ros、KDR、FMS、C-FMS、FLT3、c-Kit、JAK2、JAK3、Aurora、PDGFR、Lck、TrkA、TrkB、TrkC、IGF-IR、ALK4、ALK5和ALK或它们的组合。
• METHOD OF TREATMENT USING SUBSTITUTED IMIDAZO[1,2B]PYRIDAZINE COMPOUNDS
  申请人：Andrews Steven W.

  公开号：US20130217662A1

  公开（公告）日：2013-08-22

  Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification.

  治疗哺乳动物中的疾病或紊乱的方法，包括疼痛、癌症、炎症、神经退行性疾病、克鲁兹锥虫感染和骨溶解病，其包括向该哺乳动物投与公式I中R1、R2、R3、R4、X、Y和n在说明书中所给定的含义下的化合物的治疗有效量。